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Comparative Study
, 30 (1), 29-34

Correlation Between Serum Bactericidal Activity Against Neisseria Meningitidis Serogroups A, C, W-135 and Y Measured Using Human Versus Rabbit Serum as the Complement Source

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Comparative Study

Correlation Between Serum Bactericidal Activity Against Neisseria Meningitidis Serogroups A, C, W-135 and Y Measured Using Human Versus Rabbit Serum as the Complement Source

C J Gill et al. Vaccine.

Abstract

The surrogate of protection against invasive meningococcal disease is the presence of serum bactericidal activity (SBA) at a titer ≥4 in an assay using human serum as the complement source (hSBA). However, for various practical and logistical reasons, many meningococcal vaccines in use today were licensed based on a modified SBA assay that used baby rabbit serum as the complement source (rSBA). To assess the strength of correlation between the two assay systems for serogroups A, C, W-135 and Y, we analyzed a subset of samples from adolescent subjects enrolled in a Phase II study of Novartis' MenACWY-CRM conjugate vaccine vs. an ACWY polysaccharide vaccine; samples were analyzed in parallel using hSBA and rSBA. We compared geometric mean titers (GMTs), calculated Pearson correlation coefficients between paired hSBA and rSBA results, and calculated sensitivity/specificity and likelihood ratios for an rSBA ≥8 or ≥128 for classifying hSBA ≥4, taking hSBA as the 'gold standard'. Correlations between hSBA and rSBA ranged from 0.46 to 0.78 for serogroup C, but were weaker for serogroups A, W-135 and Y (range -0.15 to 0.57). In post vaccination samples, nearly all subjects had rSBA titers ≥8, though up to 15% remained seronegative by hSBA. In post vaccination settings, rSBA titers at ≥8 or ≥128 was highly sensitive for an hSBA titer ≥4, but non-specific. In conclusion, results generated by rSBA did not accurately classify serostatus according to hSBA for serogroups A, W-135 and Y.

Figures

Figure 1
Figure 1. Geometric mean titers (GMTs) at baseline, 1 month or 12 months after vaccination with MenACWY-CRM or MPSV-4, as measured by SBA using human (hSBA) or rabbit (rSBA) serum as the complement source
summarizes the geometric mean titers for meningococcal serogroups A, C, W-135 and Y, as measured by hSBA (Figure 1a) and rSBA (Figure 1b). For each serogroup, results are presented in pairs, representing subjects who received MenACWY-CRM or MPSV-4, and by time period: baseline, 1 month after vaccination, and 12 months after vaccination. GMTs are expressed on a log scale, with the precise value displayed over the top of each histogram.
Figure 1
Figure 1. Geometric mean titers (GMTs) at baseline, 1 month or 12 months after vaccination with MenACWY-CRM or MPSV-4, as measured by SBA using human (hSBA) or rabbit (rSBA) serum as the complement source
summarizes the geometric mean titers for meningococcal serogroups A, C, W-135 and Y, as measured by hSBA (Figure 1a) and rSBA (Figure 1b). For each serogroup, results are presented in pairs, representing subjects who received MenACWY-CRM or MPSV-4, and by time period: baseline, 1 month after vaccination, and 12 months after vaccination. GMTs are expressed on a log scale, with the precise value displayed over the top of each histogram.
Figure 2
Figure 2. Correlation coefficients between hSBA and rSBA assessments among subjects who were vaccinated with MenACWY-CRM or MPSV-4.
provides the correlation coefficients on the Y-axis for each of the four serogroups across each of the three time points (baseline, 1 month after vaccination and 12 months after vaccination). Results are displayed separately for subjects who received MenACWY-CRM on the right, and MPSV-4 on the left. The lines connecting the points on the graph are provided solely for visual ease to link a given serogroup’s responses over time, not to imply probable correlations in the intervening time periods.
Figure 3
Figure 3. Scatter plots for paired results as measured by hSBA and rSBA, assessed 1 month after vaccination with MenACWY-CRM
provides a representative sample of the matched hSBA and rSBA results from paired samples. Each point on the scatter plots represents the result of a single sample, for a single serogroup, at a single point in time (in this case, 1 month after vaccination), represented simultaneously by hSBA and rSBA. For example, the point at the bottom most left of figure 3a was a sample with a titer of 256 by rSBA and <4 by hSBA. The superimposed rectangles identify samples with discordant serostatus, i.e., where the hSBA was <1:4 but the rSBA was ≥ 8.

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